1932

Abstract

Parkinson's disease (PD) is a leading cause of neurodegeneration that is defined by the selective loss of dopaminergic neurons and the accumulation of protein aggregates called Lewy bodies (LBs). The unequivocal identification of Mendelian inherited mutations in 13 genes in PD has provided transforming insights into the pathogenesis of this disease. The mechanistic analysis of several PD genes, including α-synuclein (α-syn), leucine-rich repeat kinase 2 (LRRK2), PTEN-induced kinase 1 (PINK1), and Parkin, has revealed central roles for protein aggregation, mitochondrial damage, and defects in endolysosomal trafficking in PD neurodegeneration. In this review, we outline recent advances in our understanding of these gene pathways with a focus on the emergent role of Rab (Ras analog in brain) GTPases and vesicular trafficking as a common mechanism that underpins how mutations in PD genes lead to neuronal loss. These advances have led to previously distinct genes such as vacuolar protein–sorting-associated protein 35 (VPS35) and LRRK2 being implicated in a common signaling pathway. A greater understanding of these common nodes of vesicular trafficking will be crucial for linking other PD genes and improving patient stratification in clinical trials underway against α-syn and LRRK2 targets.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-cellbio-100818-125512
2020-10-06
2024-10-13
Loading full text...

Full text loading...

/deliver/fulltext/cellbio/36/1/annurev-cellbio-100818-125512.html?itemId=/content/journals/10.1146/annurev-cellbio-100818-125512&mimeType=html&fmt=ahah

Literature Cited

  1. Ahmadi Rastegar D, Dzamko N 2020. Leucine rich repeat kinase 2 and innate immunity. Front. Neurosci. 14:193
    [Google Scholar]
  2. Alegre-Abarrategui J, Christian H, Lufino MMP, Mutihac R, Venda LL et al. 2009. LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Hum. Mol. Genet. 18:4022–34
    [Google Scholar]
  3. Alessi DR, Sammler E. 2018. LRRK2 kinase in Parkinson's disease. Science 360:36–37
    [Google Scholar]
  4. Alvarez-Erviti L, Seow Y, Schapira AH, Gardiner C, Sargent IL et al. 2011. Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiol. Dis. 42:360–67
    [Google Scholar]
  5. Anwar S, Peters O, Millership S, Ninkina N, Doig N et al. 2011. Functional alterations to the nigrostriatal system in mice lacking all three members of the synuclein family. J. Neurosci. 31:7264–74
    [Google Scholar]
  6. Bandres-Ciga S, Diez-Fairen M, Kim JJ, Singleton AB 2020. Genetics of Parkinson's disease: an introspection of its journey towards precision medicine. Neurobiol. Dis. 137:104782
    [Google Scholar]
  7. Beilina A, Bonet-Ponce L, Kumaran R, Kordich JJ, Ishida M et al. 2020. The Parkinson's disease protein LRRK2 interacts with the GARP complex to promote retrograde transport to the trans-Golgi network. Cell Rep 31:107614
    [Google Scholar]
  8. Beilina A, Rudenko IN, Kaganovich A, Civiero L, Chau H et al. 2014. Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease. PNAS 111:2626–31
    [Google Scholar]
  9. Berndsen K, Lis P, Yeshaw WM, Wawro PS, Nirujogi RS et al. 2019. PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins. eLife 8:e50416
    [Google Scholar]
  10. Bliederhaeuser C, Grozdanov V, Speidel A, Zondler L, Ruf WP et al. 2016. Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes. Acta Neuropathol 131:379–91
    [Google Scholar]
  11. Bonet-Ponce L, Cookson MR. 2019. The role of Rab GTPases in the pathobiology of Parkinson' disease. Curr. Opin. Cell Biol. 59:73–80
    [Google Scholar]
  12. Borghi R, Marchese R, Negro A, Marinelli L, Forloni G et al. 2000. Full length α-synuclein is present in cerebrospinal fluid from Parkinson's disease and normal subjects. Neurosci. Lett. 287:65–67
    [Google Scholar]
  13. Breda C, Nugent ML, Estranero JG, Kyriacou CP, Outeiro TF et al. 2015. Rab11 modulates α-synuclein-mediated defects in synaptic transmission and behaviour. Hum. Mol. Genet. 24:1077–91
    [Google Scholar]
  14. Burré J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Südhof TC 2010. α-Synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329:1663–67
    [Google Scholar]
  15. Cao M, Wu Y, Ashrafi G, McCartney AJ, Wheeler H et al. 2017. Parkinson Sac domain mutation in synaptojanin 1 impairs clathrin uncoating at synapses and triggers dystrophic changes in dopaminergic axons. Neuron 93:882–96
    [Google Scholar]
  16. Chai YJ, Sierecki E, Tomatis VM, Gormal RS, Giles N et al. 2016. Munc18-1 is a molecular chaperone for α-synuclein, controlling its self-replicating aggregation. J. Cell Biol. 214:705–18
    [Google Scholar]
  17. Chandra S, Gallardo G, Fernández-Chacón R, Schlüter OM, Südhof TC 2005. α-Synuclein cooperates with CSPα in preventing neurodegeneration. Cell 123:383–96
    [Google Scholar]
  18. Chaugule VK, Burchell L, Barber KR, Sidhu A, Leslie SJ et al. 2011. Autoregulation of Parkin activity through its ubiquitin-like domain. EMBO J 30:2853–67
    [Google Scholar]
  19. Chen YA, Scheller RH. 2001. SNARE-mediated membrane fusion. Nat. Rev. Mol. Cell Biol. 2:98–106
    [Google Scholar]
  20. Cheng F, Li X, Li Y, Wang C, Wang T et al. 2011. α-Synuclein promotes clathrin-mediated NMDA receptor endocytosis and attenuates NMDA-induced dopaminergic cell death. J. Neurochem. 119:815–25
    [Google Scholar]
  21. Chia R, Haddock S, Beilina A, Rudenko IN, Mamais A et al. 2014. Phosphorylation of LRRK2 by casein kinase 1α regulates trans-Golgi clustering via differential interaction with ARHGEF7. Nat. Commun. 5:5827
    [Google Scholar]
  22. Chiu CC, Yeh TH, Lai SC, Weng YH, Huang YC et al. 2016. Increased Rab35 expression is a potential biomarker and implicated in the pathogenesis of Parkinson's disease. Oncotarget 7:54215–27
    [Google Scholar]
  23. Choi BK, Choi MG, Kim JY, Yang Y, Lai Y et al. 2013. Large α-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking. PNAS 110:4087–92
    [Google Scholar]
  24. Choi MG, Kim MJ, Kim DG, Yu R, Jang YN, Oh WJ 2018. Sequestration of synaptic proteins by alpha-synuclein aggregates leading to neurotoxicity is inhibited by small peptide. PLOS ONE 13:e0195339
    [Google Scholar]
  25. Chua CE, Tang BL. 2011. Rabs, SNAREs and α-synuclein–membrane trafficking defects in synucleinopathies. Brain Res. Rev. 67:268–81
    [Google Scholar]
  26. Connor-Robson N, Booth H, Martin JG, Gao B, Li K et al. 2019. An integrated transcriptomics and proteomics analysis reveals functional endocytic dysregulation caused by mutations in LRRK2. Neurobiol. Dis. 127:512–26
    [Google Scholar]
  27. Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ et al. 2006. α-Synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science 313:324–28
    [Google Scholar]
  28. Cooper JM, Wiklander PB, Nordin JZ, Al-Shawi R, Wood MJ et al. 2014. Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice. Mov. Disord. 29:1476–85
    [Google Scholar]
  29. Dalfó E, Barrachina M, Rosa JL, Ambrosio S, Ferrer I 2004a. Abnormal α-synuclein interactions with rab3a and rabphilin in diffuse Lewy body disease. Neurobiol. Dis. 16:92–97
    [Google Scholar]
  30. Dalfó E, Ferrer I. 2005. α-Synuclein binding to rab3a in multiple system atrophy. Neurosci. Lett. 380:170–75
    [Google Scholar]
  31. Dalfó E, Gómez-Isla T, Rosa JL, Nieto Bodelón M, Cuadrado Tejedor M et al. 2004b. Abnormal α-synuclein interactions with Rab proteins in α-synuclein A30P transgenic mice. J. Neuropathol. Exp. Neurol. 63:302–13
    [Google Scholar]
  32. Darios F, Ruipérez V, López I, Villanueva J, Gutierrez LM, Davletov B 2010. α-Synuclein sequesters arachidonic acid to modulate SNARE-mediated exocytosis. EMBO Rep 11:528–33
    [Google Scholar]
  33. Deniston CK, Salogiannis J, Mathea S, Snead DM, Lahiri I et al. 2020. Parkinson's disease-linked LRRK2 structure and model for microtubule interaction. bioRxiv 895367. https://doi.org/10.1101/2020.01.06.895367
    [Crossref]
  34. DeWitt DC, Rhoades E. 2013. α-Synuclein can inhibit SNARE-mediated vesicle fusion through direct interactions with lipid bilayers. Biochemistry 52:2385–87
    [Google Scholar]
  35. Dhekne HS, Yanatori I, Gomez RC, Tonelli F, Diez F et al. 2018. A pathway for Parkinson's Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain. eLife 7:e40202
    [Google Scholar]
  36. Dinter E, Saridaki T, Nippold M, Plum S, Diederichs L et al. 2016. Rab7 induces clearance of α-synuclein aggregates. J. Neurochem. 138:758–74
    [Google Scholar]
  37. Dodson MW, Leung LK, Lone M, Lizzio MA, Guo M 2014. Novel ethyl methanesulfonate (EMS)-induced null alleles of the Drosophila homolog of LRRK2 reveal a crucial role in endolysosomal functions and autophagy in vivo. Dis. Model. Mech. 7:1351–63
    [Google Scholar]
  38. Dodson MW, Zhang T, Jiang C, Chen S, Guo M 2012. Roles of the Drosophila LRRK2 homolog in Rab7-dependent lysosomal positioning. Hum. Mol. Genet. 21:1350–63
    [Google Scholar]
  39. Drouet V, Lesage S. 2014. Synaptojanin 1 mutation in Parkinson's disease brings further insight into the neuropathological mechanisms. Biomed. Res. Int. 2014:289728
    [Google Scholar]
  40. Edvardson S, Cinnamon Y, Ta-Shma A, Shaag A, Yim YI et al. 2012. A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating co-chaperone auxilin, is associated with juvenile parkinsonism. PLOS ONE 7:e36458
    [Google Scholar]
  41. El-Agnaf OMA, Salem SA, Paleologou KE, Cooper LJ, Fullwood NJ et al. 2003. α-Synuclein implicated in Parkinson's disease is present in extracellular biological fluids, including human plasma. FASEB J 17:1945–47
    [Google Scholar]
  42. El-Agnaf OMA, Salem SA, Paleologou KE, Curran MD, Gibson MJ et al. 2006. Detection of oligomeric forms of α-synuclein protein in human plasma as a potential biomarker for Parkinson's disease. FASEB J 20:419–25
    [Google Scholar]
  43. Emmanouilidou E, Melachroinou K, Roumeliotis T, Garbis SD, Ntzouni M et al. 2010. Cell-produced α-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J. Neurosci. 30:6838–51
    [Google Scholar]
  44. Fang F, Yang W, Florio JB, Rockenstein E, Spencer B et al. 2017. Synuclein impairs trafficking and signaling of BDNF in a mouse model of Parkinson's disease. Sci. Rep. 7:3868
    [Google Scholar]
  45. Fasano D, Parisi S, Pierantoni GM, De Rosa A, Picillo M et al. 2018. Alteration of endosomal trafficking is associated with early-onset parkinsonism caused by SYNJ1 mutations. Cell Death Dis 9:385
    [Google Scholar]
  46. Feng M, Hu X, Li N, Hu F, Chang F et al. 2018. Distinctive roles of Rac1 and Rab29 in LRRK2 mediated membrane trafficking and neurite outgrowth. J. Biomed. Res. 32:145–56
    [Google Scholar]
  47. Friedman LG, Lachenmayer ML, Wang J, He L, Poulose SM et al. 2012. Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of α-synuclein and LRRK2 in the brain. J. Neurosci. 32:7585–93
    [Google Scholar]
  48. Fujimoto T, Kuwahara T, Eguchi T, Sakurai M, Komori T, Iwatsubo T 2018. Parkinson's disease-associated mutant LRRK2 phosphorylates Rab7L1 and modifies trans-Golgi morphology. Biochem. Biophys. Res. Commun. 495:1708–15
    [Google Scholar]
  49. Garcia-Reitböck P, Anichtchik O, Bellucci A, Iovino M, Ballini C et al. 2010. SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson's disease. Brain 133:2032–44
    [Google Scholar]
  50. Giaime E, Tong Y, Wagner LK, Yuan Y, Huang G, Shen J 2017. Age-dependent dopaminergic neurodegeneration and impairment of the autophagy-lysosomal pathway in LRRK-deficient mice. Neuron 96:796–807.e6
    [Google Scholar]
  51. Giannandrea M, Bianchi V, Mignogna ML, Sirri A, Carrabino S et al. 2010. Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly. Am. J. Hum. Genet. 86:185–95
    [Google Scholar]
  52. Gitler AD, Bevis BJ, Shorter J, Strathearn KE, Hamamichi S et al. 2008. The Parkinson's disease protein α-synuclein disrupts cellular Rab homeostasis. PNAS 105:145–50
    [Google Scholar]
  53. Gladkova C, Maslen SL, Skehel JM, Komander D 2018. Mechanism of parkin activation by PINK1. Nature 559:410–14
    [Google Scholar]
  54. Gomez RC, Wawro P, Lis P, Alessi DR, Pfeffer SR 2019. Membrane association but not identity is required for LRRK2 activation and phosphorylation of Rab GTPases. J. Cell Biol. 218:4157–70
    [Google Scholar]
  55. Gómez-Suaga P, Rivero-Ríos P, Fdez E, Blanca Ramírez M, Ferrer I et al. 2014. LRRK2 delays degradative receptor trafficking by impeding late endosomal budding through decreasing Rab7 activity. Hum. Mol. Genet. 23:6779–96
    [Google Scholar]
  56. Gonçalves SA, Macedo D, Raquel H, Simões PD, Giorgini F et al. 2016. shRNA-based screen identifies endocytic recycling pathway components that act as genetic modifiers of alpha-synuclein aggregation, secretion and toxicity. PLOS Genet 12:e1005995
    [Google Scholar]
  57. Grey M, Dunning CJ, Gaspar R, Grey C, Brundin P et al. 2015. Acceleration of α-synuclein aggregation by exosomes. J. Biol. Chem. 290:2969–82
    [Google Scholar]
  58. Griesser E, Wyatt H, Ten Have S, Stierstorfer B, Lenter M, Lamond AI 2020. Quantitative profiling of the human substantia nigra proteome from laser-capture microdissected FFPE tissue. Mol. Cell Proteom. 19:839–51
    [Google Scholar]
  59. Guo M, Wang J, Zhao Y, Feng Y, Han S et al. 2020. Microglial exosomes facilitate α-synuclein transmission in Parkinson's disease. Brain 143:1476–97
    [Google Scholar]
  60. Gupta A, Pulliam L. 2014. Exosomes as mediators of neuroinflammation. J. Neuroinflammation 11:68
    [Google Scholar]
  61. Han C, Xiong N, Guo X, Huang J, Ma K et al. 2019. Exosomes from patients with Parkinson's disease are pathological in mice. J. Mol. Med. 97:1329–44
    [Google Scholar]
  62. Hardies K, Cai Y, Jardel C, Jansen AC, Cao M et al. 2016. Loss of SYNJ1 dual phosphatase activity leads to early onset refractory seizures and progressive neurological decline. Brain 139:2420–30
    [Google Scholar]
  63. Harper JW, Ordureau A, Heo JM 2018. Building and decoding ubiquitin chains for mitophagy. Nat. Rev. Mol. Cell Biol. 19:93–108
    [Google Scholar]
  64. Heo JM, Harper NJ, Paulo JA, Li M, Xu Q et al. 2019. Integrated proteogenetic analysis reveals the landscape of a mitochondrial-autophagosome synapse during PARK2-dependent mitophagy. Sci. Adv. 5:eaay4624
    [Google Scholar]
  65. Heo JM, Ordureau A, Paulo JA, Rinehart J, Harper JW 2015. The PINK1-PARKIN mitochondrial ubiquitylation pathway drives a program of OPTN/NDP52 recruitment and TBK1 activation to promote mitophagy. Mol. Cell 60:7–20
    [Google Scholar]
  66. Heo JM, Ordureau A, Swarup S, Paulo JA, Shen K et al. 2018. RAB7A phosphorylation by TBK1 promotes mitophagy via the PINK-PARKIN pathway. Sci. Adv. 4:eaav0443
    [Google Scholar]
  67. Herbst S, Gutierrez MG. 2019. LRRK2 in infection: friend or foe?. ACS Infect. Dis. 5:809–15
    [Google Scholar]
  68. Horgan CP, McCaffrey MW. 2011. Rab GTPases and microtubule motors. Biochem. Soc. Trans. 39:1202–6
    [Google Scholar]
  69. Houser MC, Tansey MG. 2017. The gut-brain axis: is intestinal inflammation a silent driver of Parkinson's disease pathogenesis?. NPJ Park. Dis. 3:3
    [Google Scholar]
  70. Huang C-C, Chiu T-Y, Lee T-Y, Hsieh H-J, Lin C-C, Kao L-S 2018. Soluble α-synuclein facilitates priming and fusion by releasing Ca2+ from the thapsigargin-sensitive Ca2+ pool in PC12 cells. J. Cell Sci. 131:jcs213017
    [Google Scholar]
  71. Inoshita T, Arano T, Hosaka Y, Meng H, Umezaki Y et al. 2017. Vps35 in cooperation with LRRK2 regulates synaptic vesicle endocytosis through the endosomal pathway in Drosophila. Hum. Mol. Genet 26:2933–48
    [Google Scholar]
  72. Jahn R, Scheller RH. 2006. SNAREs—engines for membrane fusion. Nat. Rev. Mol. Cell Biol. 7:631–43
    [Google Scholar]
  73. Jensen PH, Li JY, Dahlström A, Dotti CG 1999. Axonal transport of synucleins is mediated by all rate components. Eur. J. Neurosci. 11:3369–76
    [Google Scholar]
  74. Jeong GR, Jang E-H, Bae JR, Jun S, Kang HC et al. 2018. Dysregulated phosphorylation of Rab GTPases by LRRK2 induces neurodegeneration. Mol. Neurodegener. 13:8
    [Google Scholar]
  75. Jimenez-Orgaz A, Kvainickas A, Nägele H, Denner J, Eimer S et al. 2018. Control of RAB7 activity and localization through the retromer-TBC1D5 complex enables RAB7-dependent mitophagy. EMBO J 37:235–54
    [Google Scholar]
  76. Kalogeropulou AF, Zhao J, Bolliger MF, Memou A, Narasimha S et al. 2018. P62/SQSTM1 is a novel leucine-rich repeat kinase 2 (LRRK2) substrate that enhances neuronal toxicity. Biochem. J. 475:1271–93
    [Google Scholar]
  77. Kane LA, Lazarou M, Fogel AI, Li Y, Yamano K et al. 2014. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J. Cell Biol. 205:143–53
    [Google Scholar]
  78. Kazlauskaite A, Kondapalli C, Gourlay R, Campbell DG, Ritorto MSet al 2014. Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65. Biochem. J 460:12739
    [Google Scholar]
  79. Kett LR, Boassa D, Ho CC, Rideout HJ, Hu J et al. 2012. LRRK2 Parkinson disease mutations enhance its microtubule association. Hum. Mol. Genet. 21:890–9
    [Google Scholar]
  80. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y et al. 1998. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–8
    [Google Scholar]
  81. Komatsu M, Wang QJ, Holstein GR, Friedrich VL Jr., Iwata J et al. 2007. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. PNAS 104:14489–94
    [Google Scholar]
  82. Kondapalli C, Kazlauskaite A, Zhang N, Woodroof HI, Campbell DG et al. 2012. PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. Open Biol 2:120080
    [Google Scholar]
  83. Koyano F, Okatsu K, Kosako H, Tamura Y, Go E et al. 2014. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 510:162–66
    [Google Scholar]
  84. Kumar N, Leonzino M, Hancock-Cerutti W, Horenkamp FA, Li P et al. 2018. VPS13A and VPS13C are lipid transport proteins differentially localized at ER contact sites. J. Cell Biol. 217:3625–39
    [Google Scholar]
  85. Kunath T, Natalwala A, Chan C, Chen Y, Stecher B et al. 2019. Are PARKIN patients ideal candidates for dopaminergic cell replacement therapies?. Eur. J. Neurosci. 49:453–62
    [Google Scholar]
  86. Kuwahara T, Inoue K, D'Agati VD, Fujimoto T, Eguchi T et al. 2016. LRRK2 and RAB7L1 coordinately regulate axonal morphology and lysosome integrity in diverse cellular contexts. Sci. Rep. 6:29945
    [Google Scholar]
  87. Lai YC, Kondapalli C, Lehneck R, Procter JB, Dill BD et al. 2015. Phosphoproteomic screening identifies Rab GTPases as novel downstream targets of PINK1. EMBO J 34:2840–61
    [Google Scholar]
  88. Lang AE, Lozano AM. 1998. Parkinson's disease. First of two parts. N. Engl. J. Med. 339:1044–53
    [Google Scholar]
  89. Lara Ordónez AJ, Fernández B, Fdez E, Romo-Lozano M, Madero-Pérez J et al. 2019. RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase–mediated centrosomal cohesion and ciliogenesis deficits. Hum. Mol. Genet. 28:3552–68
    [Google Scholar]
  90. Lazarou M, Sliter DA, Kane LA, Sarraf SA, Wang C et al. 2015. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524:309–14
    [Google Scholar]
  91. Lee H, Flynn R, Sharma I, Haberman E, Carling PJ et al. 2020. LRRK2 is recruited to phagosomes and co-recruits RAB8 and RAB10 in human pluripotent stem cell-derived macrophages. Stem Cell Rep 14:940–55
    [Google Scholar]
  92. Lee HJ, Patel S, Lee SJ 2005. Intravesicular localization and exocytosis of α-synuclein and its aggregates. J. Neurosci. 25:6016–24
    [Google Scholar]
  93. Lesage S, Bras J, Cormier-Dequaire F, Condroyer C, Nicolas A et al. 2015. Loss-of-function mutations in RAB39B are associated with typical early-onset Parkinson disease. Neurol. Genet. 1:e9
    [Google Scholar]
  94. Lesage S, Drouet V, Majounie E, Deramecourt V, Jacoupy M et al. 2016. Loss of VPS13C function in autosomal-recessive Parkinsonism causes mitochondrial dysfunction and increases PINK1/Parkin-dependent mitophagy. Am. J. Hum. Genet. 98:500–13
    [Google Scholar]
  95. Linhart R, Wong SA, Cao J, Tran M, Huynh A et al. 2014. Vacuolar protein sorting 35 (Vps35) rescues locomotor deficits and shortened lifespan in Drosophila expressing a Parkinson's disease mutant of Leucine-Rich Repeat Kinase 2 (LRRK2). Mol. Neurodegener. 9:23
    [Google Scholar]
  96. Liu J, Zhang JP, Shi M, Quinn T, Bradner J et al. 2009. Rab11a and HSP90 regulate recycling of extracellular α-synuclein. J. Neurosci. 29:1480–85
    [Google Scholar]
  97. Liu Z, Bryant N, Kumaran R, Beilina A, Abeliovich A et al. 2018. LRRK2 phosphorylates membrane-bound Rabs and is activated by GTP-bound Rab7L1 to promote recruitment to the trans-Golgi network. Hum. Mol. Genet. 27:385–95
    [Google Scholar]
  98. Lunati A, Lesage S, Brice A 2018. The genetic landscape of Parkinson's disease. Rev. Neurol. 174:628–43
    [Google Scholar]
  99. MacLeod DA, Rhinn H, Kuwahara T, Zolin A, Di Paolo G et al. 2013. RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk. Neuron 77:425–39
    [Google Scholar]
  100. Madero-Pérez J, Fdez E, Fernández B, Lara Ordónez AJ, Blanca Ramírez M et al. 2018a. Parkinson disease-associated mutations in LRRK2 cause centrosomal defects via Rab8a phosphorylation. Mol. Neurodegener. 13:3
    [Google Scholar]
  101. Madero-Pérez J, Fernández B, Lara Ordónez AJ, Fdez E, Lobbestael E et al. 2018b. RAB7L1-mediated relocalization of LRRK2 to the Golgi complex causes centrosomal deficits via RAB8A. Front. Mol. Neurosci. 11:417
    [Google Scholar]
  102. Martin I, Dawson VL, Dawson TM 2011. Recent advances in the genetics of Parkinson's disease. Annu. Rev. Genom. Hum. Genet. 12:301–25
    [Google Scholar]
  103. Mata IF, Jang Y, Kim CH, Hanna DS, Dorschner MO et al. 2015. The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease. Mol. Neurodegener. 10:50
    [Google Scholar]
  104. Matheoud D, Cannon T, Voisin A, Penttinen AM, Ramet L et al. 2019. Intestinal infection triggers Parkinson's disease-like symptoms in Pink1−/− mice. Nature 571:565–69
    [Google Scholar]
  105. Matheoud D, Sugiura A, Bellemare-Pelletier A, Laplante A, Rondeau C et al. 2016. Parkinson's disease-related proteins PINK1 and Parkin repress mitochondrial antigen presentation. Cell 166:314–27
    [Google Scholar]
  106. Mathivanan S, Ji H, Simpson RJ 2010. Exosomes: extracellular organelles important in intercellular communication. J. Proteom. 73:1907–20
    [Google Scholar]
  107. McGough IJ, Steinberg F, Jia D, Barbuti PA, McMillan KJ et al. 2014. Retromer binding to FAM21 and the WASH complex is perturbed by the Parkinson disease-linked VPS35(D620N) mutation. Curr. Biol. 24:1670–76
    [Google Scholar]
  108. McGrath E, Waschbüsch D, Baker BM, Khan AR 2019. LRRK2 binds to the Rab32 subfamily in a GTP-dependent manner via its armadillo domain. Small GTPases https://doi.org/10.1080/21541248.2019.1666623
    [Crossref] [Google Scholar]
  109. McLelland GL, Lee SA, McBride HM, Fon EA 2016. Syntaxin-17 delivers PINK1/parkin-dependent mitochondrial vesicles to the endolysosomal system. J. Cell Biol. 214:275–91
    [Google Scholar]
  110. McLelland GL, Soubannier V, Chen CX, McBride HM, Fon EA 2014. Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control. EMBO J 33:282–95
    [Google Scholar]
  111. McWilliams TG, Barini E, Pohjolan-Pirhonen R, Brooks SP, Singh F et al. 2018. Phosphorylation of Parkin at serine 65 is essential for its activation in vivo. . Open Biol 8: https://doi.org/10.1098/rsob.180108
    [Crossref] [Google Scholar]
  112. McWilliams TG, Muqit MMK. 2017. PINK1 and Parkin: emerging themes in mitochondrial homeostasis. Curr. Opin. Cell Biol. 45:83–91
    [Google Scholar]
  113. Mir R, Tonelli F, Lis P, Macartney T, Polinski NK et al. 2018. The Parkinson's disease VPS35[D620N] mutation enhances LRRK2-mediated Rab protein phosphorylation in mouse and human. Biochem. J. 475:1861–83
    [Google Scholar]
  114. Muller MP, Goody RS. 2018. Molecular control of Rab activity by GEFs, GAPs and GDI. Small GTPases 9:5–21
    [Google Scholar]
  115. Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K, Bandres-Ciga S et al. 2019. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet Neurol 18:1091–102
    [Google Scholar]
  116. Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG et al. 2014. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat. Genet. 46:989–93
    [Google Scholar]
  117. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA et al. 2010. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLOS Biol 8:e1000298
    [Google Scholar]
  118. Ordureau A, Paulo JA, Zhang J, An H, Swatek KN et al. 2020. Global landscape and dynamics of Parkin and USP30-dependent ubiquitylomes in iNeurons during mitophagic signaling. Mol. Cell 77:1124–42.e10
    [Google Scholar]
  119. Ordureau A, Paulo JA, Zhang W, Ahfeldt T, Zhang J et al. 2018. Dynamics of PARKIN-dependent mitochondrial ubiquitylation in induced neurons and model systems revealed by digital snapshot proteomics. Mol. Cell 70:211–27.e8
    [Google Scholar]
  120. Ordureau A, Sarraf SA, Duda DM, Heo JM, Jedrychowski MP et al. 2014. Quantitative proteomics reveal a feedforward mechanism for mitochondrial PARKIN translocation and ubiquitin chain synthesis. Mol. Cell 56:360–75
    [Google Scholar]
  121. Ostermeier C, Brunger AT. 1999. Structural basis of Rab effector specificity: crystal structure of the small G protein Rab3A complexed with the effector domain of rabphilin-3A. Cell 96:363–74
    [Google Scholar]
  122. Petridi S, Middleton CA, Ugbode C, Fellgett A, Covill L, Elliott CJH 2020. In vivo visual screen for dopaminergic Rab ↔ LRRK2-G2019S interactions in Drosophila discriminates Rab10 from Rab3. . Genes Genomes Genet 10:1903–14
    [Google Scholar]
  123. Pickrell AM, Huang CH, Kennedy SR, Ordureau A, Sideris DP et al. 2015. Endogenous Parkin preserves dopaminergic substantia nigral neurons following mitochondrial DNA mutagenic stress. Neuron 87:371–81
    [Google Scholar]
  124. Pihlstrøm L, Rengmark A, Bjørnarå KA, Dizdar N, Fardell C et al. 2015. Fine mapping and resequencing of the PARK16 locus in Parkinson's disease. J. Hum. Genet. 60:357–62
    [Google Scholar]
  125. Plowey ED, Cherra SJ III, Liu Y-J, Chu CT 2008. Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J. Neurochem. 105:1048–56
    [Google Scholar]
  126. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P et al. 2017. Parkinson disease. Nat. Rev. Dis. Primers 3:17013
    [Google Scholar]
  127. Pourjafar-Dehkordi D, Vieweg S, Itzen A, Zacharias M 2019. Phosphorylation of Ser111 in Rab8a modulates Rabin8-dependent activation by perturbation of side chain interaction networks. Biochemistry 58:3546–54
    [Google Scholar]
  128. Purlyte E, Dhekne HS, Sarhan AR, Gomez R, Lis P et al. 2018. Rab29 activation of the Parkinson's disease-associated LRRK2 kinase. EMBO J 37:1–18 Corrigendum. 2019. EMBO J. 38:e101237
    [Google Scholar]
  129. Ramonet D, Daher JP, Lin BM, Stafa K, Kim J et al. 2011. Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLOS ONE 6:e18568
    [Google Scholar]
  130. Rendón WO, Martínez-Alonso E, Tomás M, Martínez-Martínez N, Martínez-Menárguez JA 2013. Golgi fragmentation is Rab and SNARE dependent in cellular models of Parkinson's disease. Histochem. Cell Biol. 139:671–84
    [Google Scholar]
  131. Richter B, Sliter DA, Herhaus L, Stolz A, Wang C et al. 2016. Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. PNAS 113:4039–44
    [Google Scholar]
  132. Rizo J, Sudhof TC. 2012. The membrane fusion enigma: SNAREs, Sec1/Munc18 proteins, and their accomplices—guilty as charged. Annu. Rev. Cell Dev. Biol. 28:279–308
    [Google Scholar]
  133. Saez-Atienzar S, Bonet-Ponce L, Blesa JR, Romero FJ, Murphy MP et al. 2014. The LRRK2 inhibitor GSK2578215A induces protective autophagy in SH-SY5Y cells: involvement of Drp-1-mediated mitochondrial fission and mitochondrial-derived ROS signaling. Cell Death Dis 5:e1368
    [Google Scholar]
  134. Sambri I, D'Alessio R, Ezhova Y, Giuliano T, Sorrentino NC et al. 2017. Lysosomal dysfunction disrupts presynaptic maintenance and restoration of presynaptic function prevents neurodegeneration in lysosomal storage diseases. EMBO Mol. Med. 9:112–32
    [Google Scholar]
  135. Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL et al. 2013. Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Nature 496:372–76
    [Google Scholar]
  136. Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C et al. 2009. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat. Genet. 41:1303–7
    [Google Scholar]
  137. Sauvé V, Sung G, Soya N, Kozlov G, Blaimschein N et al. 2018. Mechanism of parkin activation by phosphorylation. Nat. Struct. Mol. Biol. 25:623–30
    [Google Scholar]
  138. Sharma M, Burré J, Bronk P, Zhang Y, Xu W, Südhof TC 2012. CSPα knockout causes neurodegeneration by impairing SNAP-25 function. EMBO J 31:829–41
    [Google Scholar]
  139. Sharma M, Burré J, Südhof TC 2011. CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity. Nat. Cell Biol. 13:30–39
    [Google Scholar]
  140. Sliter DA, Martinez J, Hao L, Chen X, Sun N et al. 2018. Parkin and PINK1 mitigate STING-induced inflammation. Nature 561:258–62
    [Google Scholar]
  141. Søreng K, Neufeld TP, Simonsen A 2018. Membrane trafficking in autophagy. Int. Rev. Cell Mol. Biol. 336:1–92
    [Google Scholar]
  142. Soubannier V, McLelland GL, Zunino R, Braschi E, Rippstein P et al. 2012. A vesicular transport pathway shuttles cargo from mitochondria to lysosomes. Curr. Biol. 22:135–41
    [Google Scholar]
  143. Spillantini MG, Goedert M. 2018. Neurodegeneration and the ordered assembly of α-synuclein. Cell Tissue Res 373:137–48
    [Google Scholar]
  144. Steger M, Diez F, Dhekne HS, Lis P, Nirujogi RS et al. 2017. Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis. eLife 6:e31012
    [Google Scholar]
  145. Steger M, Tonelli F, Ito G, Davies P, Trost M et al. 2016. Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases. eLife 5:e12813
    [Google Scholar]
  146. Stenmark H. 2009. Rab GTPases as coordinators of vesicle traffic. Nat. Rev. Mol. Cell Biol. 10:513–25
    [Google Scholar]
  147. Sung JY, Kim J, Paik SR, Park JH, Ahn YS, Chung KC 2001. Induction of neuronal cell death by Rab5A-dependent endocytosis of α-synuclein. J. Biol. Chem. 276:27441–48
    [Google Scholar]
  148. Taylor M, Alessi DR. 2020. Advances in elucidating the function of leucine-rich repeat protein kinase-2 in normal cells and Parkinson's disease. Curr. Opin. Cell Biol. 63:102–13
    [Google Scholar]
  149. Tokuda T, Qureshi MM, Ardah MT, Varghese S, Shehab SA et al. 2010. Detection of elevated levels of α-synuclein oligomers in CSF from patients with Parkinson disease. Neurology 75:1766–72
    [Google Scholar]
  150. Tong Y, Giaime E, Yamaguchi H, Ichimura T, Liu Y et al. 2012. Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway. Mol. Neurodegener. 7:2
    [Google Scholar]
  151. Tong Y, Yamaguchi H, Giaime E, Boyle S, Kopan R et al. 2010. Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice. PNAS 107:9879–84
    [Google Scholar]
  152. Trempe JF, Sauvé V, Grenier K, Seirafi M, Tang MY et al. 2013. Structure of parkin reveals mechanisms for ubiquitin ligase activation. Science 340:1451–55
    [Google Scholar]
  153. Underwood R, Wang B, Carico C, Whitaker RH, Placzek WJ, Yacoubian TA 2020. The GTPase Rab27b regulates the release, autophagic clearance, and toxicity of alpha-synuclein. J. Biol. Chem. http://doi.org/10.1074/jbc.RA120.013337
    [Crossref] [Google Scholar]
  154. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MMK, Harvey K et al. 2004. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304:1158–60
    [Google Scholar]
  155. Vanhauwaert R, Kuenen S, Masius R, Bademosi A, Manetsberger J et al. 2017. The SAC1 domain in synaptojanin is required for autophagosome maturation at presynaptic terminals. EMBO J 36:1392–411
    [Google Scholar]
  156. Vieweg S, Mulholland K, Bräuning B, Kacharia N, Lai Y-C et al. 2020. PINK1-dependent phosphorylation of Serine111 within the SF3 motif of Rab GTPases impairs effector interactions and LRRK2-mediated phosphorylation at Threonine72. Biochem. J. 477:1651–68
    [Google Scholar]
  157. Vilariño-Güell C, Wider C, Ross OA, Dachsel JC, Kachergus JM et al. 2011. VPS35 mutations in Parkinson disease. Am. J. Hum. Genet. 89:162–67
    [Google Scholar]
  158. Vincow ES, Merrihew G, Thomas RE, Shulman NJ, Beyer RP et al. 2013. The PINK1–Parkin pathway promotes both mitophagy and selective respiratory chain turnover in vivo. PNAS 110:6400–5
    [Google Scholar]
  159. Wallings RL, Tansey MG. 2019. LRRK2 regulation of immune-pathways and inflammatory disease. Biochem. Soc. Trans. 47:1581–95
    [Google Scholar]
  160. Wang S, Ma Z, Xu X, Wang Z, Sun L et al. 2014. A role of Rab29 in the integrity of the trans-Golgi network and retrograde trafficking of mannose-6-phosphate receptor. PLOS ONE 9:e96242
    [Google Scholar]
  161. Waschbüsch D, Hübel N, Ossendorf E, Lobbestael E, Baekelandt V et al. 2019. Rab32 interacts with SNX6 and affects retromer-dependent Golgi trafficking. PLOS ONE 14:e0208889
    [Google Scholar]
  162. Waschbüsch D, Michels H, Strassheim S, Ossendorf E, Kessler D et al. 2014. LRRK2 transport is regulated by its novel interacting partner Rab32. PLOS ONE 9:e111632
    [Google Scholar]
  163. Watanabe R, Buschauer R, Böhning J, Audagnotto M, Lasker K et al. 2019. The in situ structure of Parkinson's disease-linked LRRK2. bioRxiv 837203. https://doi.org/10.1101/837203
    [Crossref]
  164. Wauer T, Komander D. 2013. Structure of the human Parkin ligase domain in an autoinhibited state. EMBO J 32:2099–112
    [Google Scholar]
  165. Wauer T, Swatek KN, Wagstaff JL, Gladkova C, Pruneda JN et al. 2015. Ubiquitin Ser65 phosphorylation affects ubiquitin structure, chain assembly and hydrolysis. EMBO J 34:307–25
    [Google Scholar]
  166. Wenzel DM, Lissounov A, Brzovic PS, Klevit RE 2011. UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids. Nature 474:105–8
    [Google Scholar]
  167. Williams ET, Chen X, Moore DJ 2017. VPS35, the retromer complex and Parkinson's disease. J. Park. Dis. 7:219–33
    [Google Scholar]
  168. Wilson GR, Sim JCH, McLean C, Giannandrea M, Galea CA et al. 2014. Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with α-synuclein pathology. Am. J. Hum. Genet. 95:729–35
    [Google Scholar]
  169. Xia Y, Zhang G, Han C, Ma K, Guo X et al. 2019. Microglia as modulators of exosomal alpha-synuclein transmission. Cell Death Dis 10:174
    [Google Scholar]
  170. Xiong Y, Coombes CE, Kilaru A, Li X, Gitler AD et al. 2010. GTPase activity plays a key role in the pathobiology of LRRK2. PLOS Genet 6:e1000902
    [Google Scholar]
  171. Yamano K, Fogel AI, Wang C, van der Bliek AM, Youle RJ 2014. Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy. eLife 3:e01612
    [Google Scholar]
  172. Yamano K, Wang C, Sarraf SA, Münch C, Kikuchi R et al. 2018. Endosomal Rab cycles regulate Parkin-mediated mitophagy. eLife 7:e31326
    [Google Scholar]
  173. Yamano K, Youle RJ. 2013. PINK1 is degraded through the N-end rule pathway. Autophagy 9:1758–69
    [Google Scholar]
  174. Yu M, Arshad M, Wang W, Zhao D, Xu L, Zhou L 2018. LRRK2 mediated Rab8a phosphorylation promotes lipid storage. Lipids Health Dis 17:34
    [Google Scholar]
  175. Zavodszky E, Seaman MNJ, Moreau K, Jimenez-Sanchez M, Breusegem SY et al. 2014. Mutation in VPS35 associated with Parkinson's disease impairs WASH complex association and inhibits autophagy. Nat. Commun. 5:3828
    [Google Scholar]
  176. Zhang Q, Pan Y, Yan R, Zeng B, Wang H et al. 2015. Commensal bacteria direct selective cargo sorting to promote symbiosis. Nat. Immunol. 16:918–26
    [Google Scholar]
  177. Zhao Y, Perera G, Takahashi-Fujigasaki J, Mash DC, Vonsattel JPG et al. 2018. Reduced LRRK2 in association with retromer dysfunction in post-mortem brain tissue from LRRK2 mutation carriers. Brain 141:486–95
    [Google Scholar]
  178. Zimprich A, Benet-Pages A, Struhal W, Graf E, Eck SH et al. 2011. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am. J. Hum. Genet. 89:168–75
    [Google Scholar]
/content/journals/10.1146/annurev-cellbio-100818-125512
Loading
/content/journals/10.1146/annurev-cellbio-100818-125512
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error